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1.
PLoS One ; 14(12): e0226626, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877172

RESUMO

Ginkgo biloba leaves extract (GBE) was subjected to neuroprotective-guided fractionation to produce eleven fractions with different polarities and constituents. The intermediate polar fraction was shown to be terpene trilactones-enriched fraction (TEGBE). Out of this fraction, pure ginkgolide B (G-B) was further purified and identified based on its spectral data. The effects of GBE and TEGBE were evaluated in comparison to that of G-B in the crush sciatic nerve injury rat model. To evaluate the neuroprotective effects, sixty Wistar male rats were randomly allocated into 6 groups: naive, sham, crush + normal saline, and three treatment groups; crush + GBE, crush + TEGBE, and crush + G-B. Treatments were given one hour following injury, and once daily for 14 days. Neurobehavioral tests, histomorphological examinations, and immunohistochemical analysis of the sciatic nerve and the spinal cord were performed at weeks 3 and 6 post-injury. GBE, TEGBE and G-B were shown to enhance the functional and sensory behavioral parameters and to protect the histological and the ultrastructural elements in the sciatic nerve. Additionally, all treatments prevented spinal cord neurons from further deterioration. It was shown that G-B has the most significant potential effects among all treatments with values that were nearly comparable to those of sham and naive groups.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Nervo Isquiático/lesões , Animais , Lesões por Esmagamento/patologia , Masculino , Traumatismos dos Nervos Periféricos/patologia , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
2.
Life Sci ; 235: 116844, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499069

RESUMO

AIMS: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice. MAIN METHODS: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/ß-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3ß, which in turn upregulated Wnt1, ß-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KEY FINDINGS: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3ß/Caspase-3 activity and enhancing the expression of Wnt1/ß-catenin/Neuro D1/Cyclin D1 and Bcl-xL. SIGNIFICANCE: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Lactonas/farmacologia , Lactonas/uso terapêutico , Neurogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
3.
Am J Chin Med ; 47(6): 1289-1305, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488032

RESUMO

The roots of Aucklandia lappa have been used in traditional medicine in Asia to treat inflammation and diseases associated with pain, including endometriosis. The aim of this study was to investigate the anti-endometriotic effect of dehydrocostus lactone, an active compound in A. lappa roots, using human endometriotic cells and macrophages stimulated by these cells. Dehydrocostus lactone induced apoptotic cell death in 12Z human endometriotic cells. Dehydrocostus lactone stimulated the activation of caspase-3, -8, and -9, while caspase inhibitors significantly reversed the dehydrocostus lactone-induced cell death in 12Z cells. In addition, dehydrocostus lactone decreased the production of PGE2 and neurotrophins (BDNF, NGF, NT3, and NT4/5), which are regarded as endometriosis-associated pain factors in human endometriotic cells. Moreover, dehydrocostus lactone inhibited the expression of M2 markers (CD206, and Trem-2), IL-10, VEGF, and MMP-2/-9 in endometriosis-associated macrophages (EAMs). Furthermore, dehydrocostus lactone inhibited the Akt and NFκB pathways in both endometriotic cells and EAMs. Taken together, our findings suggest that dehydrocostus lactone, an active compound of A, lappa, has anti-endometriotic activities via induction of apoptosis and downregulation of pain factors in endometriotic cells and inhibition of the alternative activation of EAMs.


Assuntos
Apoptose/efeitos dos fármacos , Endometriose/tratamento farmacológico , Endometriose/imunologia , Endométrio/citologia , Lactonas/farmacologia , Lactonas/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Fitoterapia , Raízes de Plantas/química , Saussurea/química , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Caspases/metabolismo , Linhagem Celular , Dinoprostona/metabolismo , Feminino , Humanos , Interleucina-10/metabolismo , Lactonas/isolamento & purificação , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Medicina Tradicional , Fatores de Crescimento Neural/metabolismo , Receptores de Superfície Celular/metabolismo , Sesquiterpenos/isolamento & purificação , Estimulação Química
4.
J Ethnopharmacol ; 245: 112186, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31472273

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sesquiterpene lactones are organic compounds derived mainly from plants that exhibit anti-inflammatory and antitumor activities being one of the key mechanism of action of NF-kB pathway and synthesis of cytokines such as IL-1 and TNF- α. AIM OF THE STUDY: The overall objective of the present study was to evaluate the anti-inflammatory action of a sesquiterpene lactone diacethylpiptocarphol (DPC) from Vernonia scorpioides (Lam.) Pers. and parthenolide (PTH) in Balb-c mice with DSS-induced colitis. MATERIALS AND METHODS: The anti-inflammatory effects of Intraperitonial administration of DPC (5 mg/kg/day) were evaluated in Balb/c mice with DSS-induced colitis, and further the body weight measurement, TNF-α and TGF-ß level was determined. RESULTS: After intraperitoneal treatment for one week, DSS-induced colitis was significantly reduced in mice treated with either of both sesquiterpenes lactones, as witnessed by reduced cellular infiltration, tissue damage, TNF-α production, and enhanced production of TGF-ß. CONCLUSIONS: Sesquiterpene lactone DPC, isolated from Vernonia scorpioides showed anti-inflammatory activity, in this experimental model of colitis the sesquiterpene lactones DPC and PTH exhibit equal anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Lactonas/uso terapêutico , Sesquiterpenos/uso terapêutico , Vernonia , Animais , Colite/sangue , Colite/induzido quimicamente , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Sulfato de Dextrana , Flores , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos BALB C , Folhas de Planta , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue
5.
Med Sci Monit ; 25: 6711-6718, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31492830

RESUMO

BACKGROUND Liver cancer is one of the most common malignancies around the world and one of the major causes of cancer related mortality. The objective of this study was to evaluate the anticancer effect of the natural compound psilostachyin-A on 5-fluorouracil-resistant human liver carcinoma cells and its effects on autophagy, cell cycle, caspase activation, and the ERK/MAPK signaling pathway. MATERIAL AND METHODS Cell Counting Kit 8 (CCK-8) assay was used to evaluate the effects on HepG2 cell viability at different doses of psilostachyin-A. Cell cycle analysis was performed using flow cytometry, and Transwell assay was used to check effects on cell invasion. Transmission electron microscopic studies were done to evaluate autophagy induced by psilostachyin-A, and the western blot method was carried out to evaluate the effects on autophagy and the ERK/MAPK signaling pathway. RESULTS CCK-8 assay revealed that the psilostachyin-A reduced the cell viability of HepG2 cancer cells in a dose dependent manner. Psilostachyin-A also reduced the colony forming potential of HepG2 cells, concentration dependently. The IC50 of psilostachyin was found to be 25 µM. The anticancer effects of psilostachyin-A were due to the induction of autophagy which was accompanied by enhancement of LC3B II expression. Psilostachyin also caused cell cycle arrest by enhancing the accumulation of HepG2 cells in the G2/M phase. Transwell assay showed that psilostachyin-A suppressed the invasion of HepG2 cells. The results also showed that psilostachyin-A could block the ERK/MAPK pathway, indicative of the cytotoxic effects of psilostachyin-A on liver cancer. CONCLUSIONS These preliminary observations suggested that psilostachyin-A might prove beneficial in the treatment of liver cancer.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fluoruracila/uso terapêutico , Lactonas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Pontos de Checagem da Fase M do Ciclo Celular , Sistema de Sinalização das MAP Quinases , Sesquiterpenos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Fluoruracila/farmacologia , Células Hep G2 , Humanos , Lactonas/química , Lactonas/farmacologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/ultraestrutura , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Ensaio Tumoral de Célula-Tronco , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Int J Clin Pract ; 73(11): e13399, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31397946

RESUMO

AIMS: To evaluate in a real-world setting the effectiveness of two drugs, orlistat and liraglutide, in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification programme. METHODS: Retrospective, observational cohort study comparing clinical outcomes of orlistat 120 mg three times a day and liraglutide (up to 3 mg daily) in adult patients with BMI ≥30 kg/m2 or ≥27 kg/m2 with at least a weight-related comorbidity who had failed to lose at least 5% of their weight after 6 months of lifestyle modification. The co-primary end-points, assessed at 3-6 months and at the end of the follow-up, were weight change from baseline, proportion of patients who lost at least 5% of their baseline weight and adjusted differences in WL between both drugs. RESULTS: Five hundred patients, 400 in the group of orlistat (age 47.0, weight 107.8 kg) and 100 in the group of liraglutide (age 51.9 years, weight 105.1 kg), were included. Treatment with both drugs significantly reduced weight, fasting plasma glucose, systolic BP, low-density lipoprotein-cholesterol and alanine transaminase over a median follow-up period of 7 months. WL with liraglutide (-7.7 kg) was significantly greater than that observed with orlistat (-3.3 kg), and more individuals lost at least 5% of their baseline weight with liraglutide (64.7%) than with orlistat (27.4%). Rates of prediabetes significantly decreased with liraglutide in comparison to orlistat. CONCLUSIONS: In this real-world study, liraglutide showed a greater effectiveness in WL compared with orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Adulto , Estudos de Coortes , Feminino , Humanos , Lactonas/uso terapêutico , Estilo de Vida , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Orlistate/efeitos adversos , Sobrepeso/tratamento farmacológico , Estudos Retrospectivos , Perda de Peso/efeitos dos fármacos
7.
Int Immunopharmacol ; 75: 105819, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31421546

RESUMO

Although several therapies are approved, none promote re-myelination in multiple sclerosis (MS) patients, limiting their ability for sustained recovery. Thus, treatment development in MS has the opportunity to tackle the challenges, including experimental therapies targeting neuroprotection and re-myelination. Here, we provide a novel therapeutic target for Ginkgolide K (GK) that is now becoming a very critical natural compound to treat demyelination and neurodegeneration. GK improves behavioral dysfunction and demyelination in cuprizone (CPZ) model, followed by the migration and enrichment of astrocytes in the corpus callosum. Both in vitro and in vivo experiments demonstrates that GK triggers the upregulation of Nrf2/HO-1 in astrocytes and inhibition of p-NF-kB/p65, which is associated with the outcome of anti-inflammation and anti-oxidation by suppressing the production of IL-6 and TNFα as well as nitric oxide and iNOS in astrocytes. Further findings suggest that IGF/PI3K, but not BDNF, was induced in the corpus callosum after GK treatment, revealing that Nrf2 activation inhibited caspase-3 and apoptosis in O4+ oligodendrocytes possibly through IGF/PI3K signaling molecules. Since the current immunomodulatory therapies for MS have failed to prevent patients from entering the progressive phase of the disease, thus targeting Nrf2 in astrocytes with GK would be an ideal strategy for myelin protection and regeneration.


Assuntos
Astrócitos/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Bainha de Mielina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Somatomedinas/metabolismo , Animais , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Cuprizona , Citocinas/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL
8.
Biomed Res Int ; 2019: 7284767, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281844

RESUMO

The potential of oxidized-LDL (Ox-LDL) to elicit inflammatory responses in macrophages leading to the atherosclerosis (AS) progression is well known. Since proprotein convertase subtilisin/Kexin-9 (PCSK-9), the posttranslational regulator of LDL-receptor, is associated with elevated LDL in the circulation, the present report was aimed to uncover the ameliorative effects of Ginkgolide B, a terpenic lactone from Ginkgo biloba, against Ox-LDL-induced alterations in cholesterol metabolism in HUVECs. Consequently, our results demonstrated that incubation with Ox-LDL significantly upregulated the PCSK-9 expression in HUVECs, which was significantly downregulated, both at mRNA and protein level, after Ginkgolide B treatment via subsequent suppression of sterol element binding protein (SREBP-2) expression. Moreover, Ginkgolide B-mediated inhibition of PCSK-9 activity was also validated by in silico methods which revealed that it interferes the PSCK-9 interaction with LDL-receptor (LDL-R). Interestingly, Ox-LDL-induced LDL-R expression was further enhanced by Ginkgolide B treatment in HUVECs. Moreover, Ginkgolide B treatment lead to downregulation of lectin-like Ox-LDL receptor (LOX-1) and NADPH oxidase (NOX-4) expression which was upregulated in Ox-LDL-treated HUVECs, along with the attenuation of mitochondrial ROS generation. Furthermore, Ginkgolide B significantly inhibited the augmented expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in Ox-LDL-activated HUVECs. Ginkgolide B also significantly ameliorated the inflammatory response in Ox-LDL-activated HUVECs by suppressing the expression of IL-1α, IL-1ß, IL-6, CXCL-1, CXCL-2, and monocyte chemotactic protein (MCP-1), at mRNA and protein level. Our in vitro and in silico study established that Ginkgolide B alleviated the Ox-LDL-induced inflammatory cascades and altered lipid metabolism in HUVECs by suppressing the PCSK-9 and, thus, could be established as a treasured alternative therapeutic candidate in the atherosclerosis management.


Assuntos
Ginkgolídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/tratamento farmacológico , Lactonas/uso terapêutico , Metabolismo dos Lipídeos , Pró-Proteína Convertase 9/metabolismo , Atorvastatina/farmacologia , Moléculas de Adesão Celular/metabolismo , Colesterol/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lactonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/química , Receptores de LDL/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
9.
Cells ; 8(7)2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323885

RESUMO

Neuroinflammation is a major cause of central nervous system (CNS) damage and can result in long-term disability and mortality. Therefore, the development of effective anti-neuroinflammatory agents for neuroprotection is vital. To our surprise, the naturally occurring molecule alantolactone (Ala) was reported to significantly inhibit tumor growth and metastasis as a result of its excellent anti-inflammatory effects. Thus, we proposed that it could also act as an anti-neuroinflammatory agent. Thus, in this study, a coculture system of BV2 cells and PC12 cells were used as an in vitro neuroinflammatory model to investigate the anti-neuroinflammatory mechanism of Ala. The results indicated that Ala downregulated the expression of proinflammatory factors by suppressing the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Further evaluation using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model supported the conclusion that Ala could (1) alleviate cerebral ischemia-reperfusion injury; (2) reduce neurological deficits, cerebral infarct volume, and brain edema; and (3) attenuate the apoptosis and necrosis of neurons. In sum, Ala demonstrates anti-neuroinflammatory properties that contribute to the amelioration of CNS damage, and it could be a promising candidate for future applications in CNS injury treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lactonas/uso terapêutico , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Ratos , Ratos Sprague-Dawley , Sesquiterpenos de Eudesmano/uso terapêutico
10.
Artif Cells Nanomed Biotechnol ; 47(1): 3087-3093, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31343277

RESUMO

Cnidium lactone is effective in the maintenance of bone mass in various osteoporosis models; however, the precise molecular mechanisms are not understood. In this study, we investigated the effects and underlying mechanisms of action of cnidium lactone on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. Cnidium lactone dose-dependently inhibited osteoclast differentiation and formation, decreased the bone-resorbing activity of osteoclasts, and downregulated the expression of osteoclast differentiation marker genes. Cnidium lactone treatment considerably reduced RANKL-induced p38 MAPK and PI3K-Akt signal activity in RAW264.7 cells. The cnidium lactone-induced osteoclastogenesis was significantly attenuated by inhibition of p38 and PI3K through pretreatment with SB203580 and LY294002, respectively. Furthermore, cnidium lactone inhibited the expression of c-Fos and NFATc-1 with dose-dependently and enhanced by SB203580 and LY294002. In conclusion, cnidium lactone inhibits osteoclast differentiation through p38 MAPK and PI3K-Akt signalling pathway/c-Fos/NFATc1 signalling pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Cnidium/química , Lactonas/farmacologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Animais , Reabsorção Óssea/tratamento farmacológico , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Lactonas/uso terapêutico , Camundongos , Fatores de Transcrição NFATC/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Oxid Med Cell Longev ; 2019: 1875471, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178951

RESUMO

Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.


Assuntos
Antagonistas Colinérgicos/uso terapêutico , Lactonas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Animais , Antagonistas Colinérgicos/farmacologia , Humanos , Lactonas/farmacologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/patologia , Sesquiterpenos/farmacologia
12.
Drugs Aging ; 36(Suppl 1): 25-44, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31073922

RESUMO

OBJECTIVE: Our aim was to assess the safety of cyclooxygenase-2 (COX-2) inhibitors in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with COX-2 inhibitors in patients with OA were eligible for inclusion. Two authors appraised titles, abstracts and full-text papers for suitability and then assessed the studies for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcomes reporting. The primary outcomes of interest were gastrointestinal disorders, cardiac disorders, vascular disorders, nervous system disorders, skin and subcutaneous tissue disorders, hepatobiliary disorders, renal and urinary disorders, as well as overall severe and serious AEs, drug-related AEs and mortality. Secondary outcomes were withdrawals due to AEs (i.e. the number of participants who stopped the treatment due to an AE) and total number of AEs (i.e. the number of patients who experienced any AE at least once). RESULTS: Database searches identified 2149 records from which, after exclusions, 40 trials were included in the meta-analysis. The use of COX-2 inhibitors in OA was associated with a significant increased risk of drug-related AEs compared with placebo (relative risk (RR) 1.26, 95% CI 1.09-1.46; I2 = 24%). The risk of upper gastrointestinal complications (including dyspepsia, gastritis and heartburn) was significantly increased with COX-2 inhibitors versus placebo (RR 1.19, 95% CI 1.03-1.38; I2 = 0%), particularly for abdominal pain, which increased by 40% with COX-2 inhibitors (RR 1.40, 95% CI 1.08-1.80; I2 = 0%). The risk of hypertension increased by 45% overall (RR 1.45, 95% CI 1.01-2.10; I2 = 25%); however, when rofecoxib was removed from the analysis the risk of hypertension in the COX-2 inhibitor group was no longer significant (RR 1.21, 95% CI 0.80-1.83; I2 = 20%). The overall risk of heart failure and edema was increased by nearly 70% with COX-2 inhibitors versus placebo (RR 1.68, 95% CI 1.22-2.31; 0%) and this level of risk did not change appreciably when rofecoxib was excluded (RR 1.67, 95% CI 1.21-2.29; 0%). CONCLUSIONS: In our analysis, COX-2 inhibitors were associated with an increased risk of upper gastrointestinal AEs, especially abdominal pain. We also found an increased risk of cardiovascular AEs with COX-2 inhibitors, namely hypertension, heart failure and edema.


Assuntos
Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Lactonas/efeitos adversos , Osteoartrite/tratamento farmacológico , Sulfonas/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Lactonas/administração & dosagem , Lactonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico , Resultado do Tratamento
13.
Cells ; 8(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083403

RESUMO

HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Graxos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lactonas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/uso terapêutico , Everolimo/farmacologia , Everolimo/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Lactonas/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Processos Neoplásicos , Células PC-3 , Transdução de Sinais/efeitos dos fármacos , Streptomyces/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
Int Immunopharmacol ; 70: 284-294, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851709

RESUMO

Multiple sclerosis is a T cell-mediated inflammatory, demyelinating disease of the central nervous system, accompanied by neuronal degeneration. Based on the anti-inflammatory effects of Ginkgolide K (GK), a platelet activating factor antagonist, we explored the possible application of GK in the treatment of MS. The results showed that GK effectively ameliorated the severity of experimental autoimmune encephalomyelitis. The intervention of GK inhibited the infiltration of inflammatory cells and demyelination in the spinal cord. At the same time, the expression of the inflammation-related molecules TLR4, NF-κB, and COX2 in the spinal cord was significantly lower in the GK-treated mice, indicating that GK intervention can inhibit the inflammatory microenvironment of the spinal cord in EAE mice. In mouse spleen lymphocytes, GK increased the proportion of regulatory T cells (Treg) and reduced the proportion of T helper 17 cells (Th17), modifying the imbalance between Th17/Treg cells. Additionally, GK shifted macrophage/microglia polarization from M1 to M2 cell type. Importantly, GK inhibited the expression of chemotactic molecules CCL-2, CCL-3 and CCL-5, thereby limiting the migration of inflammatory cells to the spinal cord. Our results provide the possibility that GK may be a promising naturally small molecule compound for the future treatment of MS.


Assuntos
Anti-Inflamatórios/uso terapêutico , Encefalomielite Autoimune Experimental/dietoterapia , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Microglia/fisiologia , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Microambiente Celular , Quimiotaxia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator de Ativação de Plaquetas/antagonistas & inibidores , Equilíbrio Th1-Th2/efeitos dos fármacos
16.
Acta Pharmacol Sin ; 40(2): 231-242, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29921883

RESUMO

Annonaceous acetogenins are a well-established family of natural products with significant bioactivities, especially high cytotoxic and antitumor activities. AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines, but its in vivo antitumor effects have not been demonstrated so far, and its anticancer mechanisms remain ambiguous. In this study, we investigated the effects of AA005 on human colon cancer cell lines in vivo. Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day, i.p.) for 21 days. AA005 administration markedly inhibited the tumor growth via promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death. Subsequent studies in human colon carcinoma cell lines SW620 and RKO in vitro revealed that after the colon cancer cells exposed to AA005, downregulation of a B-cell lymphoma 2 family protein, myeloid cell leukemia-1 (Mcl-1), was an early event due to the inhibition of Mcl-1 mRNA level and protein synthesis in a time-dependent manner. Intriguingly, knockdown of Mcl-1 using small interfering RNA markedly accelerated the nuclear translocation of AIF and upregulation of receptor interacting protein-1, and enhanced AA005-mediated lethality, whereas ectopic expression of Mcl-1 substantially attenuated AA005-mediated lethality in the colon cancer cells. Finally, silencing Mcl-1 expression markedly enhanced AA005-induced lethality in SW620 xenograft nude mice, demonstrating a pivotal role of Mcl-1 downregulation in mediating the in vivo antitumor effects of AA005. Taken together, this study demonstrates for the first time the anticancer effects of AA005 against human colon cancer cell lines in vivo, which is mediated through the downregulation of Mcl-1.


Assuntos
Acetogeninas/química , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Álcoois Graxos/uso terapêutico , Lactonas/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Animais , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Álcoois Graxos/química , Humanos , Lactonas/química , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Planta Med ; 85(2): 118-125, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30340219

RESUMO

The gut microbiota-derived metabolites of ellagitannins and green tea catechins, urolithin A (uroA) and 5-(3',4',5'-trihydroxyphenyl)-γ-valerolactone (M4), respectively, are among the main compounds absorbed into human system after ingestion of these polyphenols. The aim of this study was to establish the effects of M4, uroA, and their combinations on LNCaP cells, an androgen dependent prostate cancer in vitro model.. The LNCaP cells were incubated with increasing concentrations of tested metabolites. The cell proliferation was determined by measurement of DNA-bisbenzimide H 33 258 complexes fluorescence. The isobolographic analysis was used to establish the type of interaction between metabolites. The apoptosis, androgen receptor (AR) localization, and phosphorylation of Akt kinase were measured by flow cytometry. Prostate-specific antigen (PSA) secretion was determined by ELISA. M4 showed modest antiproliferative activity in LNCaP cells (IC50 = 117 µM; CI: 81 - 154). UroA decreased proliferation (IC50 = 32.7 µM; CI: 24.3 - 41.1) and induced apoptosis of LNCaP cells. The mixture of M4 with uroA had synergistic antiproliferative effect. Moreover, M4 potentiated inhibition of PSA secretion and enhanced retention of AR in cytoplasm caused by uroA. Interestingly, uroA increased levels of pSer473 Akt in LNCaP cells. These results show that colonic metabolites may contribute to chemoprevention of prostate cancer by varied polyphenol-rich diet or composite polyphenol preparations.


Assuntos
Antineoplásicos/uso terapêutico , Cumarínicos/uso terapêutico , Microbioma Gastrointestinal , Lactonas/uso terapêutico , Polifenóis/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colo/microbiologia , Humanos , Técnicas In Vitro , Lactonas/química , Lactonas/isolamento & purificação , Masculino
18.
Invest New Drugs ; 37(4): 636-645, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30264293

RESUMO

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Lactonas/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Lactonas/sangue , Lactonas/farmacocinética , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Camundongos Knockout , Mutação , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Sequenciamento Completo do Exoma
19.
Artigo em Inglês | MEDLINE | ID: mdl-30264682

RESUMO

BACKGROUND: The sesquiterpene lactone cynaropicrin, a major constituent of the artichoke leaves extracts, has shown several biologic activities in many preclinical experimental models, including anti-proliferative effects. OBJECTIVE: Herein we evaluated the effects of cynaropicrin on the growth of three human anaplastic thyroid carcinoma cell lines, investigating the molecular mechanism underlying its action. METHOD: MTT assay was used to evaluate the viability of CAL-62, 8505C and SW1736 cells, and flow cytometry to analyse cell cycle distribution. Western blot was performed to detect the levels of STAT3 phosphorylation and NFkB activation. Antioxidant effects were analyzed by measuring the reactive oxygen species and malonyldialdehyde dosage was used to check the presence of lipid peroxidation. RESULTS: Viability of CAL-62, 8505C and SW1736 cells was significantly reduced by cynaropicrin in a dose- and time-dependent way, with an EC50 of about 5 µM observed after 48 h of treatment with the compound. Cellular growth inhibition was accompanied both by an arrest of the cell cycle, mainly in the G2/M phase, and the presence of a significant percentage of necrotic cells. After 48 h of treatment with 10 µM of cynaropicrin, a reduced nuclear expression of NFkB and STAT3 phosphorylation were also revealed. Moreover, we observed an increase in lipid peroxidation, without any significant effect on the reactive oxygen species production. CONCLUSION: These results demonstrate that cynaropicrin reduces the viability and promotes cytotoxic effects in anaplastic thyroid cancer cells associated with reduced NFkB expression, STAT3 phosphorylation and increased lipid peroxidation. Further characterization of the properties of this natural compound may open the way for using cynaropicrin as an adjuvant in the treatment of thyroid cancer.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Lactonas/uso terapêutico , Sesquiterpenos/uso terapêutico , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antioxidantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , NF-kappa B/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
20.
Biomed Pharmacother ; 110: 155-167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30469080

RESUMO

Amphioctopus neglectus (Family: Octopodidae) is recognised as culinary delicacy in many cultures and a common sea food item on the Mediterranean and Asian coasts. Bioassay-directed fractionation of ethyl acetate/methanol extract of A. neglectus ensued in the characterisation of four previously undescribed macrocyclic lactones (1-4). These compounds exhibited potential radical-scavenging capacities (IC50 0.95-1.73 mM) along with anti-hypertensive activities (IC50 1.12-2.34 mM) against angiotensin converting enzyme (ACE). The optimum binding affinity of compound 2 (-9.84 kcal mol-1) bearing furo[1,4,8]trioxacyclohexadecine-12,19-dione moiety with ACE, along with its permissible hydrophobic-hydrophilic balance, manifested towards its greater anti-hypertensive activity compared to other analogues. The compound 2, with lesser values of the inhibitory constant (Ki = 1.0 mM) towards ACE, was found to bind more effectively to the enzyme in a non-competitive manner, and could describe the greater inhibitory ramifications than those displayed by other compounds (Ki >1.1 mM). The ex-vivo studies revealed that compound 2 imparted protective effects against angiotensin-II induced cardiac hypertrophy at 25 µg mL-1 on H9C2 cell lines, wherein about 34 percent decrease in cell area with increase in viability could be attributed to anti-hypertrophic effects of the compound administrated. These results confirmed that the protective effect of the isolated macrocyclic lactones is mediated by enhancement of anti-oxidant defense systems, which subsequently attenuates the hypertensive related disorders.


Assuntos
Angiotensina II/toxicidade , Produtos Biológicos/uso terapêutico , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Lactonas/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cardiomegalia/metabolismo , Linhagem Celular , Lactonas/química , Lactonas/isolamento & purificação , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Octopodiformes , Relação Estrutura-Atividade
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